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Identifying the Cause of Brain Cell Death in Huntington’s Disease

May 28, 2014

Hiroko Yano, Ph.D.

A Foundation-funded researcher and colleagues have reported important new insight into one of the most devastating degenerative brain disorders, Huntington’s disease. Huntington’s is believed to be caused by brain cell death, but very little is known about how or why this process starts—or how to effectively interrupt it before the disease is fatal. Currently there is no effective way to treat the illness, which has major psychiatric and neurological symptoms that worsen over time.

A faulty gene (called the huntingtin gene) has been known for decades to be the ultimate culprit in Huntington’s disease, which typically does not become symptomatic until midlife and is fatal. But the way in which this gene causes pathology in the brain has remained unknown.

Hiroko Yano, Ph.D., Washington University School of Medicine, recipient of a 2009 NARSAD Young Investigator Grant, is lead author on a paper published online May 18th in Nature Neuroscience reporting that the protein encoded by the faulty huntingtin gene—the protein produced by the gene is also called huntingtin—interacts with a complex of other proteins in a way that impairs the function of mitochondria, the ubiquitous energy factories in cells.

Prior research has associated dysfunction in mitochondria with the death of neurons in people with Huntington’s. The discoveries by Dr. Yano and colleagues demonstrate how the mitochondria in neurons cannot import essential proteins into their interior because of abnormal interaction of the mutant huntingtin protein and the TIM23 protein import complex. This current research verifies this problem in mice that model Huntington’s disease, specifically in the early stages of the illness. This suggests it has a role in causation of the full-blown illness.

The scientists also showed in cultured brain cells that model Huntington’s disease that over-expressing the TIM23 complex restored the ability of mitochondria to import proteins and prevented neurons from dying. It is not known if this approach might work in people, but it at least suggests a way of developing a therapy for Huntington’s.

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